The "Phoenix Rising" pathway of tumor repopulation during radiotherapy

放疗过程中肿瘤增殖的“凤凰涅槃”途径

• 批准号: 8184633
• 负责人: Chuan-Yuan Li
• 金额: $ 32.58万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8184633
• 关键词: Apoptosis; Biological; Caspase; Cell Death; Cells; Clinical; Development; Doctor of Philosophy; Educational process of instructing; Event; Experimental Neoplasms; Imaging Techniques; In Vitro; Investigation; Knock-out; Mediating; Mission; Modeling; Molecular; Molecular Biology Techniques; Normal tissue morphology; Paracrine Communication; Pathway interactions; Principal Investigator; Radiation Oncology; Radiation therapy; Relapse; Role; Textbooks; Transgenic Organisms; base; cancer radiation therapy; cancer therapy; caspase-3; in vivo; insight; molecular imaging; neoplastic cell; novel strategies; novel therapeutics; prevent; programs; response; small hairpin RNA; tissue regeneration; tumor

DESCRIPTION (provided by applicant): More than 40 years ago, the phenomenon of "accelerated repopulation" was described in experimental tumors undergoing radiotherapy. Today, the concept of preventing tumor cellular repopulation during treatment is a basic tenet in radiotherapy. In fact, it is one of the four all-important "R"s widely taught in radiation oncology textbooks. However, the molecular mechanisms involved in tumor repopulation are still very poorly understood. In this project, we propose a paradigm changing hypothesis with regard to the molecular mechanism of tumor repopulation during radiotherapy. Our hypothesis is that dying cells are responsible for mobilizing and stimulating the surviving tumor cells to repopulate the irradiated tumor through paracrine signaling. Our hypothesis is based on our recent discovery of the "Phoenix Rising" pathway through which caspase 3 activates paracrine signaling cascades from dying cells to stimulate tissue regeneration and the rapid proliferation of surviving tumor cells in irradiated tumors. We plan to carry out the following in-depth investigations of the roles of caspases and other factors in the "Phoenix Rising" pathway in tumor response to radiotherapy (specific aim 1). In addition, we plan to examine the roles of downstream factors of caspases in the "Phoenix Pathway" (specific aim 2). Finally we will attempt to determine if inhibition of caspases or their downstream factors is a feasible strategy to enhance cancer radiotherapy (specific aim 3). We believe our project will provide crucial insights into how tumors relapse after radiotherapy. It also has the potential to facilitate the development of new therapeutics for enhancing cancer radiotherapy. PUBLIC HEALTH RELEVANCE: In this project, we seek to carry out a major re-definition of the roles of cell death in cancer radiotherapy. We will examine a counter-intuitive hypothesis that poses a direct challenge to the existing paradigm on the biological roles of apoptosis. If proven correct, we will gain significant biological insights as well as generating exciting ideas on developing novel approaches for enhancing cancer radiotherapy. Therefore, our project is highly translatable to the fields of cancer treatment and thus relevant to the mission of NCI.

描述（由申请人提供）：40年前，在接受放疗的实验性肿瘤中描述了“加速重生”的现象。如今，预防治疗期间肿瘤细胞再植物的概念是放射疗法的基本原则。实际上，它是在放射肿瘤学教科书中广泛教授的四个最重要的“ R”之一。但是，涉及肿瘤再生的分子机制仍然非常了解。在这个项目中，我们提出了改变放疗过程中肿瘤重生的分子机制的范式。我们的假设是，垂死的细胞负责动员和刺激存活的肿瘤细胞通过旁分泌信号传导重新填充辐照肿瘤。我们的假设是基于我们最近发现的“凤凰城上升”途径的基础，caspase 3通过该途径激活了垂直细胞的旁分泌信号传导级联，以刺激组织的肿瘤中存活的肿瘤细胞的快速增殖。我们计划对胱天蛋白酶的作用和其他因素在肿瘤对放射疗法的反应中的“凤凰城崛起”途径中进行以下深入研究（特定目标1）。此外，我们计划检查胱天蛋白酶在“凤凰途径”中的下游因子的作用（特定目标2）。最后，我们将尝试确定抑制胱天蛋白酶或它们的下游因素是否是增强癌症放射疗法的可行策略（特定目标3）。我们认为，我们的项目将提供有关放射治疗后肿瘤复发的关键见解。它还有可能促进开发新的治疗剂，以增强癌症放射疗法。 公共卫生相关性：在这个项目中，我们试图重新定义细胞死亡在癌症放射疗法中的作用。我们将研究一个违反直觉的假设，该假设对现有范式构成了凋亡的生物学作用的直接挑战。如果被证明是正确的，我们将获得重要的生物学见解，并为开发增强癌症放射疗法的新方法产生令人兴奋的想法。因此，我们的项目高度转化为癌症治疗领域，因此与NCI的任务相关。